key: cord-0919376-p9dimua8
authors: Lia, Massimiliano; Berg, Thomas; Weydandt, Laura Christina; Stepan, Holger
title: Intrahepatic cholestasis of pregnancy resistant to both therapeutic plasma exchange and albumin dialysis
date: 2022-02-08
journal: BMJ Case Rep
DOI: 10.1136/bcr-2021-246318
sha: 4627d5622e8470087d894598040edc1f07e80d82
doc_id: 919376
cord_uid: p9dimua8

Intrahepatic cholestasis in pregnancy (ICP) represents, depending on its severity, a serious risk for the fetus. Those cases with unusually high bile acid levels may be resistant to pharmaceutical treatment and can be treated with plasma exchange or albumin dialysis. However, the success rate of these therapeutic options and the factors influencing therapeutic response are unknown. Furthermore, if these options fail to improve ICP and serum bile acid levels are very high (>200 μm/L), there are no clear recommendations when delivery should be planned. Here, we report a patient with severe ICP resistant to both therapeutic plasma exchange and albumin dialysis. Caesarean section was performed at 32 weeks of gestation followed by rapid remission of ICP.

Intrahepatic cholestasis in pregnancy (ICP) represents, depending on its severity, a serious risk for the fetus. Those cases with unusually high bile acid levels may be resistant to pharmaceutical treatment and can be treated with plasma exchange or albumin dialysis. However, the success rate of these therapeutic options and the factors influencing therapeutic response are unknown. Furthermore, if these options fail to improve ICP and serum bile acid levels are very high (>200 μm/L), there are no clear recommendations when delivery should be planned. Here, we report a patient with severe ICP resistant to both therapeutic plasma exchange and albumin dialysis. Caesarean section was performed at 32 weeks of gestation followed by rapid remission of ICP.

Intrahepatic cholestasis of pregnancy (ICP) is characterised by the presence of pruritus and abnormal liver function tests (including elevated bile acids) in the absence of other pathologies. 1 2 Even though pruritus represents the cardinal feature of ICP, jaundice seemed to be the more central symptom in the early literature. This condition was named 'idiopathic jaundice of pregnancy' by Eppinger, 3 or 'recurrent jaundice of pregnancy' by Svaborg. 4 However, according to more recent studies, jaundice is present in approximately 15%-20% of women with ICP. 5 6 Hence, jaundice seems to indicate severe disease while pruritus may often be the first symptom preceding the diagnosis of ICP. 1 High levels of serum bile acids and bilirubin are associated with poor neonatal outcome, including stillbirth, asphyxial events and spontaneous preterm birth. 7 8 Thus, severe ICP may not only cause symptoms in the woman, which are resistant to pharmaceutical treatment, but also represent a serious risk for the fetus. However, it is not clear how long a pregnancy complicated by severe ICP with very high bile acid levels (>200 μm/L) can be prolonged and when delivery should be pursued.

Therapeutic plasma exchange is a relatively new approach in cases of severe ICP both to treat pruritus, decrease bile acids and consequently improve fetal outcome. In some case studies, therapeutic plasma exchange has shown good effects while other investigators reported no improvement by this therapy. [9] [10] [11] [12] To this day, the rate of successful plasma exchange or the factors influencing it are unknown.

The advanced organ support (ADVOS) is an extracorporal liver support procedure based on albumin dialysis, which aims to eliminate albuminbound toxins such as bile acids. 13 However, there is no literature that reports this approach in pregnant women with ICP.

We present a G3P0 with newly appeared jaundice at 20 weeks of gestation. Fever, vomiting, abdominal pain or influenza like symptoms were not present. Her urine was dark, her stools were light and she did not report about pruritus. She had a history of Crohn's disease for which she has been taking azathioprine and mesalazine for the previous 4 years. She did not take steroid and did not have surgery for that condition in the past. Other medical conditions (eg, preexisting liver dysfunction) were absent and the pregnancy was conceived without assisted reproductive technology. She underwent amniocentesis due to hydramnios, which showed a normal karyotype. Virological examination was negative for herpes simplex virus, Epstein-Barr virus, cytomegalovirus, varicella-zoster virus, SARS-CoV-2 and hepatitis A, B, C and E. Ultrasound found no evidence of obstruction of the bilary ducts and the fetus showed normal growth and normal umbilical artery Doppler. Serum sFlt-1 and Placental Growth Factor (PlGF) were normal and proteinuria or hypertension was absent. Laboratory studies at 20 weeks of gestation returned as follows: alanine aminotransferase (ALAT) 49 U/L (reference value: 10-34 U/L), bile acids 249 μm/L (reference 

value: 0-10 μm/L), total bilirubin 292 μm/L (reference value: 0-17 μm/L). Indirect bilirubin, gamma-glutamyl transferase and prothrombin time were normal. Albumin (25 g/L) and total protein (46 g/L) were decreased.

Therapy with ursodeoxycholic acid was initiated (1 g/day until delivery) without sufficient effect, as both serum bile acids and total bilirubin remained high. At 26 weeks of gestation, therapeutic plasma exchange was begun. A total of eight cycles of plasma exchange and two cycles of albumin dialysis (ADVOS) were performed without improvement of either bilirubin or bile acids (figure 1). Additionally, rising levels of transaminases (ALAT-peak: 148 U/L) and gamma glutamyltransferase (peak: 97 U/L) were observed and, thus, the decision was made to deliver the baby by caesarean section at 32 weeks of gestation after antenatal corticosteroids. Both surgery and the neonatal course were uneventful.

The patient showed a rapid improvement of bilirubin and bile acid levels and was discharged 4 days after the operation. The genetic analysis from blood samples did not detect any gene variants associated with severe cholestatic hepatopathy. However, the patient was homozygous for a bile salt export pump variant (V444A), which is associated with low expression of the encoded export pump and, thus, may have contributed to the severity of this clinical course. 14 15 DISCUSSION ICP may be resistant to medical treatment in a significant proportion of women. 16 Especially cases with severe ICP may only respond to plasma exchange, which has been first reported by Warren and colleagues. 12 Since then, there have been various attempts to use this therapy in cases resistant to pharmaceutical treatment with encouraging results. 10 11 However, Covach and colleagues first reported a case of ICP resistant even to repeated plasma exchange. 9 Similarly, our patient also showed a lack of improvement with plasma exchange and albumin dialysis, thus raising the question of how effective this therapy truly is. Interestingly, both the case of Covach et al and our case showed some sort of pre-existing liver disease. The patient of the former case report had active hepatitis C, which has been associated with an increased severity of ICP. 17 The woman in our case report had Crohn's disease, which may have negative effects on liver function. 18 Hence, diseases afflicting the liver may limit the effect of plasma exchange in ICP. A very recent study also found that women treated with azathioprine who developed ICP often experienced a significant improvement if this medication was discontinued. 19 Consequently, the azathioprine taken by our patient may have negatively influenced the effect of therapeutic plasma exchange and albumin dialysis. However, more research is required to determine the predictive factors for successful plasma exchange, as this treatment is both costly and invasive.

Interestingly, our patient did not suffer from pruritus, which is regarded as the most characteristic symptom and a prerequisite for the diagnosis of ICP. 8 20 However, the Royal College of Obstetricians and Gynaecologists (RCOG) guideline states that otherwise unexplained elevation of bile acids or other abnormal liver parameters may be sufficient even without pruritus for the diagnosis of ICP. 2 It is, therefore, difficult to estimate the proportion of patients presenting with ICP without itch, as the definition of this condition is not universally agreed on and changed over the decades. When ICP was mainly defined by the presence of jaundice, several cases without pruritus have in fact been reported. Eliakim et al reported five cases of 'recurrent jaundice of pregnancy' of which one did not have any pruritus. 21 Svanborg and Ohlsson found that pruritus was absent in 5 out of their 22 cases. 4 Additionally, the constellation of very high bile acids and bilirubin without pruritus may not be unusual, as these parameters do not correlate well with each other. 22 23 Progesterone sulfates and autotaxin activity may play a more important role in the pathogenesis of pruritus in ICP. 24 25 Notably, the total bilirubin levels measured in this case are unusually high for ICP since concentrations reported by other authors (table 1) were not higher than 106 μm/L. 26 It is not clear when fetuses subjected to such severe ICP should be delivered. A meta-analysis by Ovadia and colleagues showed that the risk of stillbirth was best predicted by total bile acids and bilirubin. Especially bile acids higher than 100 μm/L were associated with increased risk of stillbirth. 7 Interestingly, case reports describing ICP with very high bile acids levels (over 200 μm/L) often describe non-reassuring fetal heart rate patterns around the 32nd week of gestation leading to emergency caesarean section. 10 11 27 Also, intrauterine fetal demise has been reported around this gestational week if bile acids were very high. 23 These observations could be due to a vasoconstrictive effect of bile acids on placental veins, 28 consequently causing fetal compromise. Hence, in pregnant women afflicted by ICP with very high bile acids and resistant to treatment, it seems prudent to plan delivery at 32 weeks of gestation, as emergency caesarean section and poor neonatal outcome (low Apgar, need of neonatal intensive care) have been reported by various authors (table 1) .

However, further research is needed to determine when babies subjected to such high bile acids should be delivered and which factors influence the success of plasma exchange in severe ICP.

► Intrahepatic cholestasis of pregnancy with very high bile acid levels and jaundice is rare. ► Therapeutic plasma exchange and/or albumin dialysis may not always be effective in patients with intrahepatic cholestasis of pregnancy and very high bile acid levels. ► There is a significant risk to the fetus with very high bile acid levels (over 200 μm/L) and early delivery should be considered. Most cases reported in the literature have been delivered between 31 and 33 weeks of gestation.

Obstetric cholestasis, outcome with active management: a series of 70 cases

Recurrent jaundice of pregnancy; a clinical study of twenty-two cases

The spectrum of liver and gastrointestinal disease seen in cholestasis of pregnancy

Prevalence of intrahepatic cholestasis of pregnancy in Chile

Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses

Intrahepatic cholestasis of pregnancy: relationships between bile acid levels and fetal complication rates

Intrahepatic cholestasis of pregnancy refractory to multiple medical therapies and plasmapheresis

Therapeutic plasma exchange as a novel treatment for severe intrahepatic cholestasis of pregnancy: case series and mechanism of action

Plasmapheresis in management of severe cholestasis of pregnancy

Plasmapheresis for the treatment of intrahepatic cholestasis of pregnancy refractory to medical treatment

First clinical experience in 14 patients treated with ADVOS: a study on feasibility, safety and efficacy of a new type of albumin dialysis

Interindividual variability of canalicular ATP-binding-cassette (ABC)-transporter expression in human liver

Combined mutations of canalicular transporter proteins cause severe intrahepatic cholestasis of pregnancy

A randomised controlled trial of ursodeoxycholic acid and S-adenosyl-L-methionine in the treatment of gestational cholestasis

Hepatitis C virus infection is associated with a higher incidence of cholestasis of pregnancy

Hepatobiliary dysfunction and primary sclerosing cholangitis in patients with Crohn's disease

Intrahepatic cholestasis of pregnancy associated with azathioprine: a case series

Pruritus in chronic cholestatic liver disease

Report of five cases and electron microscopic observations

Serum bile acid levels in intrahepatic cholestasis of pregnancy during treatment with phenobarbital or cholestyramine

Unusual presentation of severe intrahepatic cholestasis of pregnancy leading to fetal death

Prognostic and mechanistic potential of progesterone sulfates in intrahepatic cholestasis of pregnancy and pruritus gravidarum

Effect of plasmapheresis on cholestatic pruritus and autotaxin activity during pregnancy

Novel heterozygous ABCB4 gene mutation causing recurrent first-trimester intrahepatic cholestasis of pregnancy

Reflection on a pregnancy complicated by obstetric cholestasis

Vasoconstrictive effect of bile acids on isolated human placental chorionic veins

Severe first trimester recurrent intrahepatic cholestasis of pregnancy: a case report and literature review

Never too soon: an unusual case of intrahepatic cholestasis of pregnancy at five weeks gestation

Contributors Literature search and manuscript writing: ML and LCW. Manuscript

Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.

Massimiliano Lia http://orcid.org/0000-0001-8285-3792Copyright 2022 BMJ Publishing Group. All rights reserved. For permission to reuse any of this content visit https://www.bmj.com/company/products-services/rights-and-licensing/permissions/ BMJ Case Report Fellows may re-use this article for personal use and teaching without any further permission.

► Submit as many cases as you like ► Enjoy fast sympathetic peer review and rapid publication of accepted articles ► Access all the published articles ► Re-use any of the published material for personal use and teaching without further permission

If you have any further queries about your subscription, please contact our customer services team on +44 (0) 207111 1105 or via email at support@bmj.com.Visit casereports.bmj.com for more articles like this and to become a Fellow